Intermediates, process for preparing macrolide antibiotic agent therefrom

ABSTRACT

An erythromycin A 9-O-benzodithiol oxime intermediate represented by the following formula (III) useful for synthesis of clarthromycin and crystalline solvate thereof:                    
     Wherein, Y 1  and Y 2  are independently a hydrogen atoms or trimethylsilyl groups. And, a process for the preparation of clarithromycin using the erythromycin A 9-O-benzodithiol oxime intermediate as described in the specification.

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation ofclarithromycin represented by formula (I), which has broad antimicrobialactivity as a macrolide antibiotic agent, and a novel intermediate thatcan be used for its synthesis.

BACKGROUND OF THE PRIOR ART

To date, processes for the preparation of the above-mentioned compoundof formula (I) are described in Korean Patent Publication Nos. 91-5898,91-7572, 91-2142, 95-9367, and 96-434, Korean Laid-Open PatentPublication Nos. 90-18132 and 91-7953 as well as several literatures,for example, J. Antibiotics (Vol.46, No.4, 647(1993)), J. Antibiotics(Vol.46, No.7, 1163(1993), J. Antibiotics (Vol.37, No.2, 187(1984)),Heterocycles (Vol.36, No.2, 243(1993)), and J. Antibiotics (Vol.43, No.3, 286(1990)). These processes may be summarized in the following threeways:

<Process 1>

This process comprises protecting 3′-N,N-dimethylamino group and 2′-OHgroup of erythromycin 9-oxime derivative, wherein an OH group isprotected, with a carbobenzyloxy(Cbz) group and then methylating thehydroxyl group at the 6 position of said compound (see Korean PatentPublication Nos. 91-5898 and 91-7572). However, this process has thedisadvantages that an excess Cbz-Cl that is relatively expensive shouldbe used, and even though the deprotection is carried out by the hydrogenreaction, this reaction is not completed on account of the catalyticpoison. Further, since the methyl group of 3′-N,N-dimetylamino group ofsaid compound has to be regenerated by methylation in the final step ofthe process, it has the additional disadvantages that it is difficult toperform the process, and the process is lengthy. This process may berepresented by the following scheme:

<Process 2>

This process comprises protecting 3′-N,N-dimethylamino group oferythromycin 9-oxime derivative, wherein an OH group is protected, witha quaternary salt of an identical group (for example, benzyl group)(seeKorean Patent Publication No.91-2142). Since the deprotection in thisprocess is also carried out by using hydrogen as in process 1, it hasthe disadvantage that the reaction is not completed on account of thecatalytic poison as in Process 1. This process may be represented by thefollowing scheme:

<Process 3>

This process comprises protecting an oxime of erythromycin 9-oximederivative with a benzyl or ketal derivative, and protecting 2′-OH groupand 4′-OH group of said compound with substituted silyl groups, and thenmethylating a 6-OH group of said compound, and finally deprotecting aprotecting group of 9-oxime and trimethylsilyl group of said 2′-O- and4″-O-groups of said compound simultaneously in a relatively short stepto obtain the desired compound.(see Korean Patent Publication Nos.95-9367 and 96-434). In this case, the 9-oxime derivative used in thetrimethylsilylation of 2′-OH and 4′-OH groups should be used in the saltfree form. This process is represented by the following scheme:

In accordance with the above reaction scheme, the yield ofclarithromycin synthesized from an erythromycin A is about 45 to 50%. Inthe cases where a benzyl derivative is used to protect an oxime for theabove reaction schemes, it is difficult to perform such lengthyreactions since the deprotection is carried out by using hydrogen.Another shortcoming is that the ketal derivative, which is used toprotect an oxime, has to be used excessively (with about 2 to 3equivalents) and the total reaction time is rather lengthy. Despite ofsuch shortcoming, the ketal derivative and trimethylsilyl groups can besimultaneously eliminated by an acid treatment.

In efforts to eliminate saprophytic matters that are produced during the3 synthetic processes mentioned above, a purification step involvingprecipitation of the synthesized clarithromycin is included in the aboveprocesses. However, in most cases, there is about 10 to 20% drop in theyield. In addition, an elimination of saprophytic matters is verydifficult if the saprophytic matters having similar characteristics tothose of clarithromycin are present.

Accordingly, the inventors have extensively studied a new process forpreparing the desired compound in order to solve the above problems ofconventional methods and to increase the yield. As a result, it has beenfound that 1, 3-benzodithiol-2-ylium tetrafluoroborate(BDTF)(Syn.Commun., 471(1976)) represented by the following formula, which issimply synthesized from anthranilic acid, can be used as a protectinggroup for oxime. The present invention was made possible by means ofdeveloping a new and simple process for preparing a high yield ofclarithromycin.

SUMMARY OF THE INVENTION

It is an object of this invention to provide an erythromycin A 9-O-BDToxime intermediate represented by the following formula (III), which isuseful for the synthesis of clarithromycin prepared by reacting anerythromycin A 9-oxime or hydrochloride thereof with BDTF.

Wherein, Y₁ and Y₂ represent hydrogen atoms or trimethylsilyl groups.

Additionally, the present invention provides the compound of the formula(III) (Y₁ and Y₂ are trimethylsilyl groups) crystallized in the mixedsolvent comprising 5 to 10 parts by weight of acetone and 1 to 5 partsby weight of water. The ratio of the compound of said formula (III) andacetone is 2:1.

Furthermore, it is another object of this present invention to provide aprocess for preparation of clarithromycin, which comprises the steps of:

1) reacting an erythromycin A 9-oxime of the following formula (II) orhydrochloride thereof with 1.0 to 1.2 equivalents of 1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) in an aprotic non polarorganic solvent in the presence of 1.0 to 2.0 equivalents of pyridine toform an erythromycin A 9-O-BDT oxime derivative of the following formula(III)′ having an oxime group which is protected with a benzodithiol(BDT)group, as shown in the following scheme;

2) reacting a compound of formula (III)′ synthesized in the abovestep 1) with 3.0 to 5.0 equivalents of hexamethyldisilazane(HMDS) in thepresence of salts such as ammonium chloride, pyridine hydrochloride,pyridine p-toluene sulfonate to form2′-O,4″-O-bistrimethylsilyl-erythromycin A 9-O-BDT oxime derivative offormula (V), as shown in the following scheme;

3) methylating a 6-OH group of the compound of formula (V) synthesizedin the above step 2) with 2.0 to 3.0 equivalents of methyl iodide in anaprotic polar solvent in the presence of a strong base to form2′-O-,4″-O-bistrimethylsilyl-6-O methyl-erythromycin A 9-O-BDT oximederivative of the following formula (VII) as shown in the followingscheme;

4) deprotecting a compound of formula (VII) synthesized in the abovestep 3) to form the following formula (I).BSDA compound as shown in thefollowing scheme and;

5) simply stirring the formula (I).BSDA compound synthesized from thestep 4) in water or mixed solvent of water and water-miscible organicsolvent in the presence of an inorganic salt or a base, and thenfiltering it to form the following scheme representing the formula (I):

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, step 1 is carried out by reacting anequivalent of erythromycin A 9-oxime representing the above formula (II)or hydrochloride thereof with 1 to 2 equivalents of BDTF in an aproticnonpolar organic solvent in the presence of 1 to 2 equivalents ofpyridine to form erythromycin A-9-O-BDT oxime derivative of the aboveformula (III)′ having an oxime group, which is protected with 1,3-benzodithiol-2-ylium (BDT) group.

Step 2 is carried out by reacting the resulting compound of the formula(III)′ in the above step 1 with 3 to 5 equivalents ofhexamethyldisilazane (HMDS) in the presence of salts such as ammoniumchloride, pyridine hydrochloride, pyridine p-toluene sulfonate to form2′-O-, 4″-O-bistrimethylsilyl erythromycin A 9-O-BDT oxime derivative ofthe above formula (V).

According to the present invention, a methylation of the compound of theabove formula (V) at 6-OH group is carried out in an aprotic polarsolvent (such as DMSO or DMF), or a mixture ratio of 1:1 of said aproticpolar solvent and THF(tetrahydrofuran), or a mixture ratio of 2:2:0.3 ofsaid aprotic solvent, THF and a non-polar organic solvent (such asisopropylether or t-butylethylether) in an amount of 5 to 10 times thatof the compound of the above formula (V) to synthesize the formula(VII). The reaction, which takes about 30 minutes to 2 hours, has to becarried out in the presence of 0 to 2.5 equivalents of Et₃N, 1 to 3equivalents of a strong base such as NaH, alkoxide, KOH and NaOH, and 2to 3 equivalents of a methylating agent namely methyl iodide at atemperature of −5 to 5° C.

The compound of the above formula (VII) of the present invention is thendeprotected by using 1 to 3 equivalents of formic acid (HCO₂H) and 4 to8 equivalents of NaHSO₃, Na₂SO₃, Na₂S₂O₄, or Na₂S₂O₅, and ethanol andwater ratio of 1:1 in 5 to 10 parts by weight of the mixed solvent of1:1 of ethanol and water by refluxing with heat for 4 hours. As aresult, 1, 3-benzodithiole-2-sulfonic acid (BDSA) of clarithromycinrepresenting the above formula (I) is synthesized.

BDSA, which is synthesized by reacting a protective group, BDT, with adeoximizing agent such as NaHSO₃, Na₂SO₃, Na₂S₂O₄, or Na₂S₂O₅ in thepresence of HCOOH, forms into its salt form, represented as the aboveformula (I).BDSA when joined with a 3′-N,N-dimethylamino group. Afterthe reaction is completed and the temperature is lowered to roomtemperature, the desired compound, which is crystallized in the reactionsolvent, is then purified. As a result, the separation of the desiredcompound from the other by-products becomes very feasible. In this case,since the reaction between a BDT group and a deoximizing agent occursfirst in the order of deprotection, oxime is synthesized without havingany protection. Clarithromycin is synthesized as a result of adeoximization and an elimination of trimethlysilyl group in the finalstep.

According to a process of the present invention, the above formula(I).BDSA is reacted with an inorganic salt such as K₂CO₃, Na₂CO₃, or KOHto remove BDSA in a neutralizing reaction and finally a pure crystalform of clarithromycin representing the above formula (I) is obtained.

It is yet another object of this invention to provide another processfor the preparation of clarithromycin of formula (I) by addinghexamethyldisilazane (HMDS) to erythromycin A 9-oxime representing theformula (II) or hydrochloride thereof to form2′-O,4″-O-bistrimethylsilyl-erythromycin A 9-oxime derivative of formula(IV) in place of the above step 1), and reacting2′-O-,4″-O-bistrimethylsilyl-erythromycin A 9-oxime derivative offormula (IV) in an aprotic organic solvent such as MC in the presence ofpyridine with 1 to 2 equivalents of BDTF to form a quantitative yield of2′-O-,4″-O-bistrimethylsiliyl-erythromycine A 9-O-BDT oxime derivativeof formula (V) in place of the above step 2), as shown in the followingscheme;

Once the compound of the above formula (V) is mixed and dissolved in amixed solvent of 1 to 5 parts by weight of water and 5 to 10 parts byweight of acetone (preferably in the mixture ratio of 3:10) to form acrystalline solvate comprising the compound of the above formula (V) andacetone in 2:1 ratio.

The following are examples to illustrate the present invention infurther detail but they do not limit the scope of the invention inanyway.

EXAMPLE 1 (1) Preparation of 2′-O,4″-O-bistrimethylsilylerythromycin A9-Oxime

157 g(0.2 mole) of erythromycin A 9-oxime.HCl and 5.4 g(0.1 mole) ofammonium chloride were placed into a 2 l flask, and 600 ml ofdimethylformamide were added thereto. 217 ml(1 mole) ofhexamethyldisilazane (HMDS) were slowly added to the mixture, and thenstirred at a temperature of 35 to 40° C. for 3 hours. 30 ml of waterwere added to the mixture, and then stirred for one hour. Thereafter,600 ml of water were further added thereto. After further stirring themixture for 30 minutes, 150 ml of 2N-NaOH were added thereto, and themixture was then extracted with 600 ml of dichloromethane. An aqueoussolution layer was again extracted with 2 l of dichloromethane. Afterthe organic layers were combined, the mixture was washed with 200 ml ofsaturated saline, solution, and then dehydrated with anhydrous MgSO₄.The solvent was removed under reduced pressure to obtain 170.5 g of thetitle compound as a foam(yield 95.4%).

1H NMR(CDCl₃) δ 0.16(s,9H, −OTMS), 0.19(s,9H, −OTMS)

(2a) Preparation of 2′-O-,4″-O-bistrimethylsilyl-erythromycin A 9-O-BDTOxime

8.93 g(10 mmole) of 2′-O-,4″-O-bistrimethylsilyl-erythromycin A 9-oximeprepared in the above 1) were dissolved in 40 ml of dichloromethane, and2.52 g(1.05 mmole) of BDTF were then added thereto at a temperature of20 to 25° C. 1.13 ml(14 mmole) of pyridine were slowly added to themixture, and then stirred for 30 mins. 50 ml of methylene dichloride and50 ml of water were added to the mixture, and then extracted. Theorganic layer was washed with saturated saline solution, dehydrated withanhydrous MgSO₄, filtered, and then dried to obtain 10.25 g of the titlecompound as a foam(yield 98.0%).

1H NMR(CDCl₃) δ 7.37(m,2H), 7.11(m,2H), 6.88(s,1H), 3.28(s,3H),2.63(s,6H), 0.16(s,18H)

(2b) Preparation of 2′-O-,4″-O-bistrimethylsilylerythromycin A 9-O-BDTSolvate with Oxime and Acetone Ratio of 2:1

30.75 ml of water was slowly added to the desired compound of the abovein the form of a foam that has already been dissolved in 102.5 ml ofacetone. The resulting solid is then placed in an ice bath, stirred foran hour, filtered and dried. As a result,2″-O-,″4-O-bistrimethylsilyl-erythromycin A 9-O-BDT oxime 8.95 g(85.0%yield) of solvate with oxime and acetone ratio of 2:1 was obtained.

¹H-NMR(CDCl₃) δ 7.37(m,2H), 7.11(m,2H), 6.88(s,mH), 3.28(s,3H),2.63(s,6H), 2.10(s,6H), 0.16(s,18H)

(3) Preparation of 2′-O-,4″-O-bistrimethylsilyl-6-O-methyl-erythromycinA 9-O-BDT Oxime

Before adding 10.45 g(10 mmole) of2′-O,4″-O-bistrimethylsilyl-erythromycin A 9-O-BDT oxime prepared in theabove 2) to 160 ml of mixture of anhydrous THF, anhydrous DMSO andt-butylmethylether(2:2:0.3). 1.39 ml of Et₃N was added to the mixture.The temperature was adjusted to 0° C. At this point, 0.98 g(15 mmole) ofKOH and 1.25 ml(20 mmole) of methyl iodide were added thereto. Thereaction was completed after stirring the mixture for an hour.Thereafter, the mixture was sequentially extracted with 100 ml of hexaneand 100 ml of water. The organic layer was washed with about 10% salinesolution, dehydrated with anhydrous MgSO₄, and then filtered. Thesolvent was removed under reduced pressure to obtain 10.46 g of thedesired compound in the form of a foam(yield 98.8%).

1H NMR(CDCl₃) δ 7.05˜7.40(m,4H), 6.89 (s,1H), 3.31(s,3H), 2.63(s,3H),2.22(s,6H), 0.17(s,9H), 0.09(s,9H)

(4) Preparation of 1, 3-Benzodithiol-2-sulfonic Acid Salt

10.60 g(10 mmole) of2′-O-,4″-O-bistrimethylsilyl-6-O-methyl-erythromycin A 9-O-BDT oximeprepared in the above 3) were dissolved in 50 ml of ethanol, and 50 mlof water were then added thereto. 0.57 ml(15 mmole) of formic acid and4.16 g(40 mmole) of sodium hydrogen sulfate(NaHSO₃) were added to themixture, and then refluxed with heat for 2 hours. 0.19 ml(0.5 mmole) offormic acid was added additionally to the reaction mixture and refluxedagain with heat for another 2 hours. After the reaction was completed,the temperature of the reaction mixture was lowered to room temperature.The resulting solid was filtered and dried to obtain 5.80 g(59.1% yield)of the desired compound.

¹H NMR(CDCl₃+DMSO-d₆) δ 7.18(m,2H), 7.01(m,2H), 5.61(s,1H), 5.05(d,1H),4.89(d,1H), 4.55(d,1H), 3.97(m,2H), 3.70(m,5H), 3.40(m,2H), 3.32(s,3H),3.02(s,8H), 2.83(dd,6H), 2.59(m,1H), 2.34(d,1H), 1.40˜1.95(m,6H),1.37(s,3H), 1.10˜1.35(m,26H), 0.85(t,3H)

(5) Preparation of Clarithromycin

9.82 g(10 mmole) of the resulting compound from the above step 4 wasadded to 19.64 ml of ethanol and 49.1 ml of water and stirred. 2.76 g ofK₂CO₃ dissolved in 49.1 ml of water was slowly added to the mixturethereto. The resulting crystal, which was then placed in 14 mg of K₂CO₃dissolved in 98.2 ml of water and stirred for 5 minutes, was filteredand dried to obtain 7.14 g(95.5% yield) of the desired compound.

¹H-NMR(CDCl₃) δ 5.08(d,1H), 4.93(d,1H), 4.44(d,1H), 4.02(m,1H),3.99(s,1H), 3.78(m,2H), 3.67(d,1H), 3.33˜3.46(m,2H), 3.34(s,3H),3.19(t,2H), 3.06(s,3H), 2.89˜3.02(m,2H), 2.89(m,1H), 2.58(m,1H),2.40(m,2H), 2.29(s,6H), 1.93(d,1H), 1.40˜1.95(m,6H), 1.42(s,3H),1.10˜1.35(m,26H),0.85(t,3H)

EXAMPLE 2

10.33 g(97.5% yield) of 2′-O-,4″-O-bistrimethylsilylerythromycin A9-O-BDT oxime compound was obtained by the same method as in Example 1except for 0.8 g(20 mmole) of 60% NaH used in the place of KOH in thestep (3) of the above Example 1.

EXAMPLE 3

7.49 g(10 mmole) of erythromycin A 9-oxime were dissolved in 40 ml ofmethylene dichloride, and 1.13 ml(14 mmole) of pyridine were addedthereto. 2.64 g(11 mmole) of BDTF was added portion-wise to the mixtureat room temperature, and then stirred at the same temperature for 30minutes. After the reaction was completed, 40 ml of methylene dichlorideand 60 ml of water were added to the mixture, and then extracted. Theorganic layer was washed with 10% saline solution, dehydrated withanhydrous MgSO₄, and then filtered. The solvent was removed underreduced pressure to obtain 8.76 g of the desired compound in the form ofa foam(yield 97.2%). The rest of the procedure was performed in the samemanner as in the step (2) of the above Example 1.

1H NMR(CDCl₃) δ 7.30(m,2H), 7.13(m,2H), 6.87(s,4H), 3.30(s,3H),2.50(s,6H)

EXAMPLE 4

9.01 g(10 mmole) of A 9-O-BDT oxime prepared in the step (2) of theabove Example 1 and Example 3 and 0.8 g(15 mmole) of ammonium chloridewere added to 27 ml of dimethylformamide. 8.44 ml (40 mmole) ofhexamethyldisilazane(HMDS) were slowly added to the mixture, and thenstirred at a temperature of 40 to 50° C. for 5 hours. The mixture wassequentially extracted with 60 ml of water and 60 ml of dichloromethane,and the aqueous layer was again extracted with 20 ml of dichloromethane.The organic layers were combined, washed with 20 ml of saturated salinesolution, and then dehydrated with anhydrous MgSO₄. The solvent wasremoved under reduced pressure to obtain 9.53 g of the desired compoundin the form of foam (yield 91.2%). The rest of the procedure wasperformed in the same manner as in the step (3) of the above Example 1.

EXAMPLE 5

5.67 g(57.7% yield) of 1, 3-benzodithiol-2-sulfonic acid was obtained bythe same method as in Example 1 except that 8.2 g(40 mmole) of Na₂S₂O₄used in the place of NaHSO₃ in the step (4) of the above Example 1.

EXAMPLE 6

5.49 g(55.9% yield) of 1, 3-benzodithiol-2-sulfonic acid was obtained bythe same method as in Example 1 except that 7.84 g(40 mmole) of Na₂S₂O₅used in the place of NaHSO₃ in the step (4) of the above Example 1.

EXAMPLE 7

5.62 g(57.2% yield) of 1, 3-benzodithiol-2-sulfonic acid was obtained bythe same method as in Example 1 except that 5.04 g(40 mmole) of Na₂SO₃used in the place of NaHSO₃ in the step (4) of the above Example 1.

The following are the effects of this present invention:

First of all, in the prior art, the use of benzyl derivative as aprotecting group of oxime makes the process difficult since thedeprotection should be carried out by the hydrogenation reaction usingthe catalyst, and this deprotection is not completed on account of thecatalytic poison. Furthermore, in case where the ketal derivative isused as a protecting group of oxime during the deprotection, it has theadvantage that a trimethylsilyl group and an oxime may be simultaneouslydeprotected. However, it also has some disadvantages such as anexcessive use of ketal derivative and an extended reaction time.However, according to the present invention, the protection of an oximemay easily be carried out in near quantitative manner by using1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) which is simplysynthesized from anthranilic acid. Furthermore, since the said BDTFgroup used as a protecting group of oxime may be simultaneously removedtogether with trimethylsilyl group and oxime group when the deprotectionis carried out under acidic conditions, it simplifies the process, andit is thus possible to obtain about 52% yield of the desired compound offormula (I) by performing this short process involving erythromycin A.

Secondly, in the prior art, since a step involving crystallization inethanol was necessary after the deprotection for the purification of thepurest form of clarithromycin, about 10 to 20% drop in the yield hasincurred as a result. However, in the present invention, the formationof the salts by joining the resulting clarithromycin from thedeprotection and the resulting BDSA from the reaction between aprotective group and a deoximizing agent is carried out and cooled atroom temperature for an immediate crystallization of the salts in thereaction mixture for a separation of a purest form of crystals.

Consequently, once the salts are eliminated by neutralization,clarithromycin having a high purity and yield can be obtained and thepurification step can be significantly simplified.

Thirdly, while a protective group of oxime in the prior art has onlyprotected oxime and allowed a selectivity for introduction of a methylgroup, a BDTF group that has been used in this present invention isresponsible for not only protecting oxime and allowing the selectivity,but also forming a BDSA group by reacting with deoximizing agent such asNaHSO₃, Na₂SO₃, Na₂S₂O₄ and Na₂S₂O₅ and forming clarithromycin salt thatcan immediately be extracted from the reaction mixture as crystals toeffectively indicate that the purification step can be significantlysimplified.

What is claimed is:
 1. An erythromycin A 9-O-benzodithiol oximeintermediate represented by the following formula (III) useful forsynthesis of clarthromycin and crystalline solvate thereof;

wherein, Y₁ and Y₂ are independently a hydrogen atom or trimethylsilylgroup.
 2. The intermediate compound and crystalline solvate thereofaccording to claim 1, wherein said crystalline solvate consists of saidintermediate compound of formula (III), in which Y₁ and Y₂ aretrimethylsilyl groups, and acetone in the ratio of 2 to
 1. 3. A processfor the preparation of clarithromycin of formula (I), which comprisesthe steps of: 1) reacting an erythromycin A 9-oxime of the followingformula (II) or hydrochloride thereof with 1.0 to 1.2 equivalents of1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) in an aprotic nonpolar organic solvent in the presence of 1.0 to 2.0 equivalents ofpyridine to synthesize an erythromycin A 9-O-BDT oxime derivative offormula (III)' having an oxime group which is protected with1,3-benzodithiol (BDT) group;

2) reacting a compound of formula (III)′ synthesized in the step 1) with3.0 to 5.0 equivalents of hexamethyldisilazane (HMDS) in the presence ofsalts selected from the group consisting of ammonium chloride, pyridinehydrochloride, and pyridine p-toluene sulfonate to form2′-O-,4″-O-bistrimethylsilylerythromycin A 9-O-BDT oxime derivative offormula (V);

3) methylating a 6-OH group of the compound of formula (V) synthesizedin the step 2) with methyl iodide in a solvent in the presence of strongbase to form 2′-O-,4″-O-bistrimethylsilyl-6-O-methyl-erythromycin A9-O-BDT oxime derivative of formula (VII);

4) deprotecting the compound of formula (VII) synthesized in the step 3)to form the following formula (I).BDSA; and

5) stirring the compound of formula (I).BDSA synthesized in the step 4)in water or a mixture of water and water-miscible organic solvent in thepresence of an inorganic salt or a base and then filtering it to form aclarithromycin representing the following formula (I)


4. The process according to claim 3, wherein said solvent used in thestep 3) is selected from an aprotic polar solvent selected from DMF orDMSO, a mixture of said aprotic polar solvent and THF (1:1), or amixture of said aprotic polar solvent, THF, and a non-polar organicsolvent selected from isopropylether or t-butylmethylether (2:2:0.3),and the methylation of the compound of formula (V) in the step 3) iscarried out at a reaction temperature of −5 to 5° C. for 30 minutes to 2hours with 2.0 to 3.0 equivalents of methyl iodide as a methylatingagent under said solvent in an amount of 5 to 10 times of the compoundof formula (V) and 1.0 to 3.0 equivalents of a strong base selected fromthe group consisting of KOH, alkoxide and NaH in the presence of 0 to2.5 equivalents of Et₃N.
 5. The process according to claim 3, whereinthe water-miscible organic solvent in the step 5) is ethanol.
 6. Theprocess according to claim 3, wherein the deprotection of the step 4) iscarried out by using 1.0 to 3.0 equivalents of formic acid and 4.0 to8.0 equivalents of NaHSO₃, Na₂S₂O₄, Na₂S₂O₅ or Na₂SO₃ in 5 to 10 partsby weight of the mixture ratio of 1:1 of ethanol and water, and cooledat room temperature before being crystallized.
 7. The process accordingto claim 3, wherein the neutralizing reaction of the step 5) is carriedout by preparing the solution of the compound of the formula (I). BDSAby mixing one part by weight of said compound and 10 to 20 parts byweight of ethanol in a mixture ratio of 1:1, and adding 3 to 5 parts byweight of the solvent which includes 1 to 2 parts by weight of aninorganic salt or base to said solution.
 8. A process for thepreparation of clarithromycin of the following formula (I), whichcomprises the steps of: 1) adding hexamethyldisilazane (HMDS) toerythromycin A 9-oxime or hydrochloride thereof to form2′-O-4″-O-bistrimethylsilyl-erythromycin A 9-oxime derivative of thefollowing formula (IV);

2) reacting 2′-O′-4″-O-bistrimethylsilyl-erythromycin A 9-oximederivative of formula (IV) in an aprotic organic solvent in the presenceof pyridine with a BDTF to form2′-O′-4″-O-bistrimethylsilyl-erythromycin A 9-O-BDT oxime derivative ofthe following formula (V);

3) methylating a 6-OH group of the compound of formula (V) synthesizedin the step 2) with methyl iodide in an aprotic polar solvent in thepresence of strong base to form2′-O-,4″-O-bistrimethylsilyl-6-O-methyl-erythromycin A 9-O-BDT oximederivative of the following formula (V);

4) deprotecting the compound of formula (VII) synthesized in the step 3)to form the following formula (I). BDSA; and

5) stirring the compound of formula (I). BDSA synthesized in the step 4)in water or a mixture of water and water-miscible organic solvent in thepresence of an inorganic salt or a base and then filtering it to form aclarithromycin representing the following formula (I)